Immunoglobulin Heavy/Light Chain Measurements During Monitoring Provide Prognostic Information of Relapse After Therapy in Myeloma Patients

Abstract Abstract 3964 Introduction: Monitoring multiple myeloma (MM) patients is required to help guide therapy and assess response. Currently the most commonly employed tests to monitor MM patients include serum protein electrophoresis (SPEP), immunofixation (IFE), 24hr urine and serum free light chain (FLC) analysis. Whilst electrophoretic tests are adequate for IgG MM, they may be inadequate for IgA MM where the monoclonal immunoglobulin co-migrates with other serum proteins (∼60% of cases). Recently the inclusion of FLC testing to identify patients in stringent complete response (sCR) has been recommended. Novel nephelometric reagents have become available that can quantify IgA kappa and IgA lambda immunoglobulins (HLC) in serum. Here we assess the use of these tests at maximum response to detect residual disease and comment on the prognostic value of sCR. Patients, materials and methods:196 IgA MM patient samples recruited from the MRC IX trial were assessed at maximum response. Briefly, patients were randomised on to intensive (I: induction therapy with CVAD or CTD followed by high-dose melphalan and ASCT) and non-intensive (NI: clodronate or zoledronic with MP or CTDa) arms. Median age was 59 years (range: 37–71) and 74 years (range: 65–89) for patients in the I and NI arms, respectively. 31% patients in the I arm and 39% in the NI arm presented with stage III disease. Samples were taken 3 months after autologous stem cell transplant or maximum response and analysed nephelometrically using serum FLC and HLC immunoassays. Ratios for both FLC and HLC were compared to normal ranges (FLC normal ratio= 0.256–1.65, IgAkappa/IgAlambda normal ratio=0.8–2.04). Additionally, isotype-matched immunoparesis was described as <0.48 g/L IgAkappa and <0.36g/L IgAlambda. Results were compared to SPEP, IFE and total immunoglobulin assays (where immunoparesis was described as <6g/L IgG and <0.4g/L IgM). 2-year progression free survival (PFS) was determined using Kaplan Meier analysis (SPSS v 19.0). Results: 3 months post-therapy, patient responses were: I arm: progressive disease (PD): n=1(<1%); minimal response (MR): n=1(<1%); partial response (PR): n=10(8%); very good partial response (VGPR): n=35(29%); complete response (CR): n=13(11%); sCR: n=58(48%); for two patients no data was available; NI arm: progressive disease (PD): n=3(4%); stable disease (SD): n=5(7%); MR: n=10(13%); PR: n=31(41%); VGPR: n=16(21%); CR: n=11(15%). Within the 2-year follow up, 41% patients in the I arm and 46% in the NI arm relapsed. Median PFS was not significantly different between the two arms (not reached v 7 months, p=0.65). Response (3VGPR) was not associated with PFS in either arm (I, p=0.717; NI, p=0.236). By contrast, achievement of a sCR (p=0.013) was significantly associated with longer PFS in the I arm and tended towards significance in the NI arm (p=0.063). An abnormal HLC ratio was associated with shorter PFS in both arms (I, p=0.002; NI, p=0.032). In all patients achieving a 3VGPR, an abnormal HLC ratio was associated with shorter PFS (p>0.0001). Similarly, in patients achieving a 3CR an abnormal HLC ratio was also associated with shorter PFS (p=0.04). Furthermore, patients achieving a CR where both FLC and HLC ratios were normal had a significantly longer PFS than those with an abnormal FLC or HLC ratio (median PFS not reached v 18 months, p=0.007). Isotype-matched immunoparesis was associated with shorter PFS in all patients achieving a CR (p=0.061). By contrast, systemic immunoparesis of either IgG or IgM immunoglobulins were not associated with PFS (p=0.525 and p=0.964, respectively). Discussion: Novel therapies have dramatically improved MM patient outcomes, however improvements in the assessment of those outcomes has not followed a similar trajectory. Here we present data suggesting immunoglobulin HLC ratios may be better markers of residual disease than electrophoretic methods. In addition a response category based on normalisation of both FLC and HLC ratios may be more valuable than sCR. Finally, the identification of isotype matched immune reconstitution as a marker of outcome suggests a preferential suppression of immunoglobulin production not previously reported. Conclusion: Normalisation of the FLC and HLC ratio at maximum response is a better assessment of disease than IFE. Further work is required to validate these results and to assess FLC and HLC ratios against multi-parametric flow cytometry. Disclosures: Young: Binding Site: Employment.

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Role of Second Stem Cell Transplant in Patients with Amyloidosis Who Are Refractory or Relapsing.

Blood ◽

10.1182/blood.v106.11.5469.5469 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5469-5469

Author(s):

Morie Abraham Gertz ◽

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Suzanne R. Hayman ◽

Shaji K. Kumar ◽

...

Keyword(s):

Stem Cell ◽

Light Chain ◽

Stem Cell Transplant ◽

Complete Response ◽

Free Light Chain ◽

High Dose ◽

Cell Transplant ◽

High Dose Therapy ◽

Single Organ

Abstract Introduction: Stem cell transplant is an increasingly widely applied technique for managing amyloidosis. As in multiple myeloma, the treatment would not be expected to be curative and patients would be expected to relapse in most instances. In addition, approximately one-third of patients fail to respond to initial therapy. The role of second transplantation in treatment failures or patients who relapse is reviewed. Patients: Of 242 patients undergoing high dose conditioning and stem cell transplantation for amyloidosis (AL) at the Mayo Clinic, 6 subsequently underwent a second transplant. Results: Patient 1, who had single organ renal amyloid nephrotic syndrome responded and relapsed at 73 months, received a second stem cell transplant achieving a hematologic complete response with normalization of a markedly elevated pre transplant free light chain (59 to 1.9 mg/dL) and is alive at 12 months. Patient 2 relapsed 42 months after transplant for single organ renal amyloidosis; the second stem cell transplant, has normalized his free light chain ratio reduced his urinary protein loss from 5450 to 1482 mg/day and he is alive 21 months following his second transplant (63 months overall). Patient 3 relapsed 34 months after a response of renal and cardiac amyloidosis. After transplant two, he failed to achieve a 50% reduction in his free light chain, began hemodialysis 7 months post transplant and died one year post transplant. Patient 4 with single organ cardiac involvement relapsed 30 months following his first transplant and died on day +5 of his second transplant of an acute pulmonary embolus. Patient 5 was a response failure after his first transplant, had a second transplant 35 months later, having failed Dexamethasone followed by Melphalan/Dexamethasone therapy, and died 3 months later of progressive disease. Patient 6 had single organ vascular involvement manifest by calf and thigh claudication and failed to respond with his first transplant with a persistently elevated free light chain. The second transplant was performed six months after the first without further free light chain reduction and persistent claudication at 11 months. Conclusion: Patients who failed to achieve a hematologic response after a first transplant appear not to benefit from a second course of high dose therapy. Among 4 patients who were previously responsive and relapsed, one achieved a hematologic complete response, one achieved a hematologic partial response, and two died. The two patients achieving a second hematologic response had the longest response duration (73 and 42 months) following their first transplant, and the second response presumably reflects favorable (indolent; non proliferative) biology of the underlying plasma cell dyscrasia. High dose therapy and stem cell transplant may be an effective salvage regimen for patients who responded to a first transplant and whose response lasted greater than 36 months.

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Ad-ISF35-Transduced Autologous Cells In Combination with Fludarabine, Cyclophosphamide, Rituximab (FCR) Induces Complete and Partial Responses In a Phase 1b Study for Patients with Fludarabine-Refractory and/or Del(17p)/p53-Defective Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v118.21.168.168 ◽

2011 ◽

Vol 118 (21) ◽

pp. 168-168

Author(s):

Januario E. Castro ◽

Lee Schwartzberg ◽

Javier Pinilla-Ibarz ◽

Johanna Melo-Cardenas ◽

Juan S. Barajas-Gamboa ◽

...

Keyword(s):

Adverse Events ◽

Cytotoxic Activity ◽

Residual Disease ◽

Complete Response ◽

Chemotherapeutic Agents ◽

Lymphocytic Leukemia ◽

High Dose ◽

Cell Transplant ◽

Phase 1B

Abstract Abstract 168FN2 CLL cells with del(17p) typically have loss of functional p53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40 ligand (CD154) are induced to express pro-apoptotic factors to overcome resistance to the cytotoxic activity of p53-dependent drugs, such as fludarabine. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine-refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted. Autologous CLL cells transduced ex vivo with a replication-defective adenovirus vector encoding a membrane-stable, re-engineered form of CD154 (Ad-ISF35) are administered, followed by standard courses of FCR. Subjects with fludarabine-refractory and/or del(17p) CLL received three IV doses (one dose every two weeks) of 3×108autologous Ad-ISF35-transduced CLL cells. Two weeks following the third dose of Ad-ISF35-transduced cells, subjects receive up to six monthly cycles of FCR. Study endpoints include analysis of safety and efficacy. Nine (9) subjects have been enrolled and treated on study. Median age was 63 (range 48–70). All subjects were del(17p) (range 14–96%), and included treatment naïve (n=4) and previously treated (n=5) subjects. The number of prior treatments range from 0–5, including three subjects that previously received fludarabine-containing regimens. The overall response rate was 67% with 56% of subjects achieving a complete response (CR), including 3 CRu pending bone marrow assessment. Two subjects with a marked percentage del(17p) (range 63–66%) continue to have an ongoing complete response (CR) after a median follow up of >2 years, and no detectable minimal residual disease (MRD) in one subject. Three subjects that showed disease progression were treated with either alemtuzumab (1 subject) or ofatumumab plus high dose methylprednisolone therapy followed by allogeneic stem cell transplant (2 subjects). We observed clinical responses not only after FCR but also after infusion of Ad-ISF35-transduced cell. These ISF35-specific responses included reductions in absolute lymphocyte counts in all subjects (decrease from baseline 4–89%), and decreased lymphadenopathy (>50% reduction) in 78% of the subjects (decrease from baseline 19–100%). Infusion of Ad-ISF35-transduced cells plus FCR has been well-tolerated. The primary non-hematologic adverse events have been flu-like symptoms following infusion of Ad-ISF35 transduced cells. This includes transient grade I/II fever (89%), fatigue (56%) and chills (56%). The primary hematologic adverse events have been cytopenias following FCR treatment, including grade III/IV neutropenia (33%) and anemia (22%). Grade I/II hypophosphatemia (56%) following ISF35 has been observed and this might be related to increased serum cytokine levels following Ad-ISF35-transduced cell administration. Correlative studies on CLL cells obtained before and after infusions of Ad-ISF35-transduced CLL cells demonstrated that CLL cells prior to treatment were refractory to the cytoxic effects of P53-dependent drugs (e.g. F-ara-A). However, the CLL cells obtained after treatment with Ad-ISF35-transduced CLL had increases of p73, p21 and Bid and became sensitive in vitro to the cytotoxic activity of F-ara-A. We also observed up-regulation of costimulatory molecules (CD80, CD86, CD54) and death receptors (CD95). The majority of subjects developed antibodies against adenovirus with neutralizing activity. However, they did not developed antibodies against human CD154. Subjects also showed increases in TNFα, IL-6 and IL12 after infusion of Ad-ISF35 transduced cells. In conclusion, the combination of Ad-ISF35 transduced CLL cells plus FCR appears to be well-tolerated and highly effective in CLL patients with fludarabine-refractory disease and/or del(17p). The CR rate that we have observed in this high-risk CLL population is higher than those reported in the literature and makes our results very encouraging. Correlative data suggest that Ad-ISF35 promotes upregulation of costimulatory and death receptor molecules as well as pro-apoptotic proteins that may overcome resistance to FCR in vivo. These encouraging data suggest the combination of Ad-ISF35 plus chemoimmunotherapy could offer an effective treatment option for patients who otherwise would be resistant to standard forms of therapy. Disclosures: Cantwell: Memgen, LLC: Employment, Patents & Royalties.

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Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN

Blood Advances ◽

10.1182/bloodadvances.2020003642 ◽

2021 ◽

Vol 5 (4) ◽

pp. 1092-1096

Author(s):

Peter M. Voorhees ◽

Cesar Rodriguez ◽

Brandi Reeves ◽

Nitya Nathwani ◽

Luciano J. Costa ◽

...

Keyword(s):

Multiple Myeloma ◽

Residual Disease ◽

Survival Rates ◽

Final Analysis ◽

Complete Response ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Best Response

Abstract The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

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Outcomes of Second Autologous Peripheral Blood Stem Cell Transplant in Multiple Myeloma Patients with Renal Dysfunction

Blood ◽

10.1182/blood.v124.21.5894.5894 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5894-5894

Author(s):

Lakshminarayanan Nandagopal ◽

J. Christine Ye ◽

Richard Manasa ◽

Muneer H. Abidi ◽

Lois Ayash ◽

...

Keyword(s):

Partial Response ◽

Creatinine Clearance ◽

Renal Dysfunction ◽

Stable Disease ◽

Progressive Disease ◽

Disease Status ◽

Patient Characteristics ◽

Complete Response ◽

Cell Transplant ◽

Good Partial Response

Abstract Second autologous stem cell transplant (ASCT) is a treatment option for multiple myeloma (MM) patients (pts) who have disease progression after first ASCT. About 20% of MM pts have evidence of renal dysfunction and many more develop it subsequently. Outcomes of second ASCT in pts with renal dysfunction have not been described. We identified 18 pts at our institution who underwent a second ASCT for relapsed MM and had evidence of renal dysfunction (creatinine clearance ≤ 60ml/min/1.73m2). Pts who underwent a planned tandem transplant were excluded from this analysis. Patient characteristics are shown in Table 1. The median age of pts was 61 years (range, 49-72). The median time between first and second ASCT was 49.8 months (range, 19.2-81.9). Ten pts received one chemotherapy regimen while nine pts received two or more chemotherapy regimens between first and second ASCT. The chemotherapy regimens used between first and second transplant included IMid based (n=6), proteosome inhibitor based (n=3) and combination of both (n=9). Approximately half of the pts had progressive disease at the time of second ASCT. Median creatinine clearance at the time of second ASCT was 43.5 ml/min//1.73m2. All pts received G-CSF 5µg/Kg from day + 6 till absolute neutrophil count was ≥1500/µL, norfloxacin, acyclovir and fluconazole were used for antimicrobial prophylaxis during the hospitalization. One pt was dialysis dependent. Patients received a median dose of melphalan of 140mg/m2 (range 100-200 mg/m2). Median follow up post second ASCT was 17.1 months (range, 2.4- 100). One pt died 74 days after the transplant due to multi- organ failure. Disease status at day 100 post ASCT is shown in Table 2. Thirteen of 17 pts had a partial response or better after second ASCT. Of 17 evaluable pts at day 100, twelve had an upgrade from the disease response category achieved with the last regimen used prior to second ASCT while five pts had stable disease response. Three pts received maintenance therapy after the second ASCT with bortezomib(n=2) and lenalidomide (n=1). Figures 1 and 2 show the overall survival (OS) and relapse free survival (RFS). Median RFS was 22.2 months and median OS was 27 months. The outcomes of patients with renal dysfunction who underwent ASCT in the era of novel agents at our institution are comparable to those reported for second ASCT. The transplant related mortality was not higher than expected and the median PFS of about 2 years makes the option of second ASCT in this group of patients a valuable treatment modality. The utility of maintenance therapy after the second ASCT is not established, but may have contributed to the durable responses seen in some pts assessed herein and deserves to be investigated further. Table 1: Pt Characteristics (N=18) Patient Characteristics N (%) Median Age (range) 61 years(49-72) Median Time from First ASCT (range) 49.8 months(19.2-81.9) Gender Male 9(50%) Females 9 (50%) Race Caucasians 13 (72%) Others 5 (28%) Disease status at time of ASCT PD 9 (50%) SD 5 (28%) PR 1 (5.5 %) VGPR 2 (11%) CR 1 (5.5%) Median creatinine clearance (range) 43.5 (5-59) Subtype IgG Kappa 10 (56%) IgG Lambda 6 (33%) Kappa Light Chain 2 (11%) Cytogenetic Risk Standard 10 (56%) High Risk 4(22%) Unknown 4 (22%) Melphalan Dose median mg/m2( range) 140 (100-200) {100(2pts), 140(10pts), 180(1pt), 200(4pts)} Median CD 34 Cell dose x106/kg (range) 4.66(2.6-27.5) Median Engraftment Day (range) WBC 11 (9-16) Platelets 21 (12-61) Median Days of Hospitalization (range) 19(11-74) PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; WBC White blood cells Table 2 Disease status at Day 100 post ASCT Disease status at Day 100 post ASCT N(%) CR 4 (22%) VGPR 4 (22%) PR 5 (28%) SD 3 (17%) PD 1 (5.5%) NOT AVAILABLE * 1 (5.5%) PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; *Pt died at day 74 post second ASCT PD: Progressive disease, SD: Stable disease; PR: Partial response; VGPR: Very good partial response; CR: complete response; * Pt died at day 74 post second ASCT Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Transplantation for Immunoglobulin Light Chain Amyloidosis. A Statistical Analysis of Factors Predicitng Outcome In Over 400 Patients

Blood ◽

10.1182/blood.v116.21.3557.3557 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3557-3557 ◽

Cited By ~ 1

Author(s):

Morie Abraham A. Gertz ◽

Martha Lacy ◽

Angela Dispenzieri ◽

Shaji Kumar ◽

Francis Buadi ◽

...

Keyword(s):

Partial Response ◽

Median Survival ◽

Light Chain ◽

Research Funding ◽

Complete Response ◽

Free Light Chain ◽

Response To Therapy ◽

High Dose ◽

Best Response ◽

Response Group

Abstract Abstract 3557 Introduction: Autologous stem cell transplantation for patients with amyloidosis results in high reported hematologic and organ response rates compared with conventional chemotherapy. Patients: Four-hundred and thirty-four patients have undergone transplantation between March 8, 1996, and April 13, 2010 Table 1. Clinical parameters seen in patients with amyloid are given in Table 2. The overall day-100 mortality seen in this group of patients is 44 of 434 patients (10%). Results: The most important determinant of outcome is stage defined by BNP and troponin levels. Figure 1 demonstrates the survival for patients for all 3 cardiac stages. Troponin <.035; NT-proBNP <332. Stage 1 both low, Stage 3 both elevated. The survival of all patients based on whether they achieved a complete response, a partial response (>50%), or no response was analyzed. Median survival has not been reached for the complete response group, is 107 months for the partial response group, and is 32 months for the no response group (p<0.0001). Figure 2, divides the patients at the median dFLC level of 13.5 mg/dL demonstrating that for patients with a higher level of free light chain, the median survival is 87.6 months and has not been reached for those with a lower level of free light chain. A proportional hazards model for variables that impact on survival was done in all patients, and the only relevant predictor of outcome was stage (p<0.0001). When the same analysis was performed using a landmark of 6 months, the only predictor of outcome was stage (p=0.0005). When best response was incorporated into the landmark model, it was the strongest predictor of survival. The amyloid stage predicted survival (p= 0.0005), and the best response to therapy (p <0.0001). When the same analysis was performed in the entire group of 434, stage and best response each remained significant (p<0.0001). Discussion: There is a high response rate associated with high-dose therapy that was not observed in the melphalan and prednisone era. For eligible patients who can be transplanted safely, high-dose melphalan is an effective therapy for many patients with amyloidosis. Best response and stage at diagnosis are the best predictors of overall survival. Disclosures: Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

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Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001752 ◽

2021 ◽

Vol 9 (4) ◽

pp. e001752

Author(s):

Rivka R Colen ◽

Christian Rolfo ◽

Murat Ak ◽

Mira Ayoub ◽

Sara Ahmed ◽

...

Keyword(s):

Partial Response ◽

Stable Disease ◽

Progressive Disease ◽

Tumor Response ◽

Complete Response ◽

Classification Model ◽

P Value ◽

Rare Cancer ◽

Rare Cancers ◽

Contrast Enhanced Ct

BackgroundWe present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.MethodsThe study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 “controlled disease” (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.FindingsThe 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.ConclusionOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.InterpretationOur radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.

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Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8004 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8004-8004

Author(s):

Philippe Moreau ◽

Pieter Sonneveld ◽

Keyword(s):

Interim Analysis ◽

Residual Disease ◽

Progression Free Survival ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

Second Primary ◽

Cell Transplant ◽

Open Label ◽

Depth Of Response

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P <0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P< 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P <0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P <0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

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Adaptation of chemotherapy to the decline tumor markers in patients with poor prognosis nonseminomatous germ cell tumors:Real-world French experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.385 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 385-385

Author(s):

Marion Rolland ◽

Sara Faouzi ◽

Leonor Chaltiel ◽

Clement Dumont ◽

Lionnel Geoffrois ◽

...

Keyword(s):

Germ Cell ◽

Tumor Marker ◽

Tumor Markers ◽

Poor Prognosis ◽

Complete Response ◽

High Dose Chemotherapy ◽

High Dose ◽

Cell Transplant ◽

French Experience ◽

Prognosis Group

385 Background: Personalized chemotherapy based on tumor marker decline is the new standard in poor prognosis germ-cell tumor in Europe since 2014 (GETUG 13, Lancet, Fizazi et al). The purpose of this study was to analyze the reproducibility of the princeps study in patients not selected in clinical routine between 2014 and 2018. Methods: Patients (pts) were eligible if they had at least one criteria of IGCCCG classification for poor prognosis group. They had to be treated according the study terms of GETUG 13 study and did not received prior treatment. They had to received 1 BEP (Bleomycin, Etoposide, Cisplatin). Tumor markers (HCG and AFP) were dosed between day 18 and 21. Then, they received 3 additional BEP if they had favorable tumor marker decline or intensive chemotherapy if they had unfavorable decline. Results: This retrospective study included 104 patients in 14 french centers treated between 2013 and 2018: 22,1 % (n = 23) in the favorable group (Fav), 77,9 % (n = 81) in the unfavorable group (Unfav). Thirty-two pts had PS ≥ 2. In Unfav, there were more pts with HCG > 50 000 UI/L (44,2 % vs 13 %, p = 0,0067), neutrophil-to-lymphocyt ratio was also higher (median 6,4 vs 4,5, p = 0,0199). At cycle 1, all pts received BEP in Fav and 87,5 % (n = 70) in Unfav. After chemotherapy and surgery, 65,2 % in Fav and 41,3 % in Unfav obtained complete response. At 30 months (median follow-up), Fav-OS was 80,5 % (IC95% 55,8 – 92,2) and Unfav-OS was 64,4 % (IC95% 52 – 74,4). At 30 months, rates were 69,6 % (IC95% 46,6 -84,2) and 63.5 % (IC95% 51,9 – 73) respectively. In GETUG 13 study, 3-years OS was 84 % in Fav and 73 % on Unfav; 3-years PFS was 70 % and 59 % respectively. Seven pts died because of toxicity in Unfav (No one in Fav). Neuropathy, anemia and thrombopenia were more frequent in Unfav. Salvage high-dose chemotherapy with stem-cell transplant was required in 4 (66,7 %) pts in Fav and 8 (36,4 %) pts in Unfav. Conclusions: This study showed a reproducibility of the princeps study in terms of PFS and OS. Toxicity seemed more important in real world. For the congress, results will be reported with 50 additional pts.

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Delivering HDAC over 3 or 5 days as consolidation in AML impacts health care resource consumption but not outcome

Blood Advances ◽

10.1182/bloodadvances.2020002511 ◽

2020 ◽

Vol 4 (16) ◽

pp. 3840-3849 ◽

Cited By ~ 1

Author(s):

Pierre-Yves Dumas ◽

Sarah Bertoli ◽

Emilie Bérard ◽

Thibaut Leguay ◽

Suzanne Tavitian ◽

...

Keyword(s):

Health Care ◽

Residual Disease ◽

Total Duration ◽

Length Of Hospital Stay ◽

Standard Of Care ◽

Complete Response ◽

Health Care Resource ◽

Resource Consumption ◽

High Dose ◽

Treatment Regimens

Abstract Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients.

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Treatment of Relapsed Myeloma in a Patient With Renal Insufficiency

Journal of Clinical Oncology ◽

10.1200/jco.2017.77.6419 ◽

2018 ◽

Vol 36 (20) ◽

pp. 2012-2016

Author(s):

Joan Bladé ◽

Laura Rosiñol ◽

María Teresa Cibeira ◽

Carlos Fernández de Larrea

Keyword(s):

Serum Creatinine ◽

Light Chain ◽

Progressive Disease ◽

M Protein ◽

Bone Lesions ◽

High Dose ◽

Kappa Light Chain ◽

Urine Protein ◽

Urine Protein Excretion ◽

Protein Excretion

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 45-year-old man was diagnosed in March 2010 with stage III immunoglobulin G kappa multiple myeloma (MM) after presenting with bone pain as a result of multiple lytic bone lesions and T12 vertebral collapse. Laboratory work-up showed a serum M protein of 72 g/L and a 24-hour kappa light-chain urine protein excretion of 730 mg, hemoglobin of 10.2 g/dL, serum albumin of 49 g/L, serum β2-microglobulin of 6.4 mg/L, serum creatinine level of 1.6 mg/dL with an estimated glomerular filtration rate (eGFR) of 47 mL/min/1.73 m2, and normal serum calcium and lactate dehydrogenase (LDH) levels. His bone marrow contained 58% plasma cells, which showed the 17p deletion abnormality (Fig 1). He was treated with vertebroplasty and alternating chemotherapy with carmustine, vincristine, cyclophosphamide, melphalan, and prednisone and vincristine, carmustine, doxorubicin and dexamethasone. Because of progressive disease, salvage therapy with bortezomib and dexamethasone was administered with no response. The patient was then switched to lenalidomide and dexamethasone, which yielded minimal response. He underwent autologous stem-cell transplantation (ASCT) with melphalan 200 mg/m2 as high-dose therapy in February 2011, which led to a partial response, but in December 2011, progressive disease was documented, and the patient was enrolled in a clinical trial of carfilzomib monotherapy, with stable disease for 33 cycles. In October 2014 serum M protein rose to 38.6 g/L, with 24-hour kappa light-chain urine protein excretion of 840 mg, serum creatinine of 2.1 mg/dL, and an eGFR of 41 mL/min/1.73 m2. He presented to discuss ongoing treatment options.

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